In the
not too distant future the entire biomedical literature will be available on line. In the
meantime, we can collectively move in that direction if individuals will take "time off" to place papers which they think
particularly important in their personal web-pages. Beginning with a seminal paper by the
founder of theoretical immunology, Paul Ehrlich, this web page provides an eclectic set of
papers with an obvious personal bias. However, I have provided, and will attempt to
increase the number of, links with other sites on the topic.

Honoured President, my lords and
gentlemen, -- It is to me the very greatest honour
that I have been summoned here by your most highly esteemed Society, which for more than
two centuries has represented and still represents the centre of the scientific life of
England, in order that I may deliver the Croonian Lecture. I consider I am not so much
personally concerned in the honour that you bestow on me, and that I shall not err if I
see in it a recognition of the scientific path which I, in company with many others, have
sought to follow, and which in your eyes suffices to place the field in which I work on a
footing alongside of exact science. It is an extreme pleasure for me to have the privilege
of addressing so many medical colleagues with whom for so many years I have been bound in
close ties of friendship, and who have always been the first to welcome and to give
recognition to the results of my work.

Since
Jenner made his great discovery of the protective action of vaccinia against small-pox, a
century has passed away. During these years that terrible scourge of mankind has been
almost completely eradicated from the civilised world.

The beneficial
consequences of Jenner's discovery are so evident to all who have any wish to properly
appreciate them, that one wonders why, during so great a portion of the long period of 100
years, they were allowed to stand alone, without any endeavour being made to induce an
artificial immunity in the case of other infectious diseases. This is all the more
remarkable because Jenner's discovery demonstrated in their entirety those essential
principles which, in later times, have been established for other infectious
diseases.

In the
first place, it was shown that by the use of an attenuated
virus, which of itself was non-injurious to the organism, it was possible
to ward off the disease caused by the virulent virus.
Jenner also established -- what is most important from the practical point of view -- that
by the inoculation of the weakened poison there was produced not only an immediate, but
also an enduring, protection.

That
Jenner's discovery remained so isolated was due essentially to the fact that the
theoretical conceptions of the cause and nature of infectious diseases made no advance
during the subsequent decades; indeed, it would be an interesting topic for some historian
of medicine to trace, step by step, the gradual advance in the knowledge of infectious
diseases during the past century.[For Rinderpest
1866(Click Here)]

Schwann's classical investigations must be regarded as the first link in the long chain.
Schwann it was who, in an unusually brilliant manner, first demonstrated that the
decomposition of organic bodies in the processes of fermentation and putrefaction was
never spontaneous, but constantly arose through the agency of micro-organisms coming from
without. This line of investigation reached its zenith in the fundamental work of Pasteur,
of which the first and the greatest result -- Lister's method of wound treatment -- worked
a revolution in surgery. Then followed the profound investigations of Koch on Anthrax, and
the pure cultivation of the most important pathogenic bacteria.

The work of Pasteur and of Koch afforded the first basis on which the study of
artificial immunity could be again undertaken. The possibility of voluntarily producing a
number of the most important infectious diseases of men and animals, and of modifying at
will pure cultivations of bacteria, either, according to Jenner's precedent, by passage
through the animal body, or otherwise in artificial culture media, laid the foundation on
which advancement could proceed.

Pasteur himself was the first, after Jenner,
to produce an artificial immunity by using an attenuated virus; and he was also able to
introduce the procedure to some extent into practice with most beneficial results.

Still, the theoretical
explanations of all these facts lagged far behind their practical effects. The very able
investigations of Metchnikoff and his theory of phagocytosis were, to many investigators,
inconclusive.

With Behring's discovery, that in the blood serum of animals immunised against
diphtheria and tetanus, there were contained bodies which were able to specifically
protect other animals against the toxines of these diseases, an altogether new factor was
introduced into the question. This remarkable discovery seemed at one stroke to open up an
entirely new and extremely promising prospect of immunising mankind against the majority
of the infectious diseases.

It was, therefore, somewhat disappointing when
there did not follow, on the successful practical application of diphtheria antitoxic
serum, a rapid succession of similar achievements. It may with truth be said, that during
recent years there has been somewhat of a standstill in the following-out of a work at
first so enthusiastically received. By purely empirical methods, e.g., by the production
and use of sera of very great antitoxic value, the results attained showed no improvement.

Better
success was only to be hoped for when, by an accurate knowledge of the theoretical
considerations underlying the question of immunity, explanations of the previous
ill-success were forthcoming. Impelled by these considerations I laboured for years
trying to shed some light into the darkness that shrouded the subject.

In all exact work with chemical bodies -- for only as such can we regard the
toxines produced by the living bacteria -- the first desideratum in the investigation is
the exact numerical determination of action and counteraction. The words of the gifted
natural philosopher Clerk Maxwell, who said that if he were required to symbolize the
learning of our time he would choose a metre measure, a clock and a kilogramme weight, are
equally apposite in reference to progress in the field of inquiry in which we are at
present interested.

And so, at the very beginning of my
theoretical work on immunity, I made it my first task to introduce measures and figures
into investigations regarding the relations existing between toxine and antitoxine.
From the outset it was clear that the difficulties to come were extremely great.
The toxines, i.e., the poisonous products of bacteria, are unknown in a pure condition.
So great is their potency, that we are obliged to assume that the strongest solid (feste)
poisons which are obtained by precipitating toxic bouillon with ammonium sulphate,
represent nothing more than indifferent materials, peptones and the like, to which the
specific toxine attaches itself in mere traces beyond the reach of weighing; for up
to the present time, by the purely chemical methods of weighing and measuring, it has
impossible to ascertain anything as to their presence or the intensity of their action.

Their presence [the presence of toxins]is only betrayed by the
proof of their specific toxicity on the organism. For the exact determination e.g., of the
amount of toxine contained in a culture fluid, the essential condition was that the
research animals used should exhibit the requisite uniformity in the susceptibility to the
poison. Uniformity is not to be observed in the reaction of the animal body to all
toxines.

Fortunately in
the case of one important body of this nature, viz., the diphtheria toxine, the conditions
are such that the guinea-pig affords for investigations the degree of accuracy necessary
in purely chemical work. For other toxines this accuracy in measuring the toxicity
cannot be attained. It was necessary for me to try to eliminate, as far as possible, the varying factor
of the animal body, and bring the
investigations more nearly into line with the conditions necessary for experiments of a
chemical nature.

In the course of these
endeavours it was shown that it was possible to obtain in a comparatively simple manner an
insight into the theoretical considerations necessary to a proper understanding of
immunity, by means of test-tube experiments with suspended animal tissues. The relations
were simplest in the case of red blood corpuscles.
On them, outside the body, the action of many blood poisons, and of their antitoxines, can
be most accurately studied, e.g., the actions of ricin, eel-serum, snake-poison, tetanus
toxine, etc.

In an
experiment of this kind, in which are employed a series of test-tubes containing definite
quantities of suspended blood corpuscles,
each test-tube represents as it were a research animal, uniform in any one series, and one
that can be reproduced at will. By means of these test-tube experiments,
particularly in the case of ricin, I was able, in the first place, to determine that they
yielded an exact quantitative representation of the course of the processes in the living
body. The demonstration of this fact formed the basis of a more extended application of
experiments of this nature.

It was
shown that the action of
toxine [antigen] and antitoxine [antibody]
took place quantitatively as in the animal body. Further, these experiments yielded a striking series of facts of importance for
the theoretical valuation of the reaction between toxine and antitoxine. It was proved in
the case of certain toxines -- notably tetanus toxine -- that the action of antitoxines is
accentuated or diminished under the influence of the same factors which bring about
similar modifications in chemical processes -- warmth accelerates, cold retards the
reaction, and this proceeds more rapidly in concentrated than in dilute solutions.

These facts,
first ascertained by means of test-tube experiments, have since been confirmed by Behring
and Knorr for tetanus within the animal body, and by Martin and Cherry in the case of
snake-venom.* {Footnote: Note during revision.-- The credit of first
drawing attention to these points belongs to Professor Fraser, who, as far back as 1896,
carried out extraordinarily precise experiments on the conditions of neutralisation in
respect both of time and of amount of snake-poison and anti-venin (Lecture, Royal
Institution, March 20, 1896).} The knowledge
thus gained led easily to the inference that to render toxine innocuous by means of
antitoxine was a purely chemical process, in which biological processes had no share. Yet
again insurmountable obstacles seemed to present themselves to this conclusion.

It must be postulated that
in chemical processes the bodies sharing in the action react with one another in definite
equivalent quantities. This proposition appeared, however, not to hold in the case of the
action of antitoxins on diphtheria toxine. When, in the case of Diphtheria toxines of
different stocks, that quantity of toxine bouillon which is exactly neutralised by a
certain definite quantity of diphtheria antitoxine (the official German immunity unit, as
laid down for the control examination of sera) was determined, so that every trace of
toxic action was abolished, the figures obtained were not in accord.

Of one toxine
bouillon 0.2 c.c., of another 2.5 c.c., were so neutralised by one immunity unit. Such a
relation need not have given rise to surprise, because it was well known that the
diphtheria bacillus, according to outside circumstances, yields in the bouillon very
different quantities of toxine. It was therefore allowable to infer that the different
quantities of toxine bouillon, which were saturated by one immunity unit, were exact
expressions of the toxicities of the various bouillons, or, to use other words,
indifferently whether the bouillon was strongly or feebly toxic, the same multiple of the
minimal lethal dose would be constantly neutralised by one immunity unit, so that in every
case the law of equivalent proportions would hold good.

But when looked into more closely,
the relations showed themselves to be by no means so simple. In what manner could
one obtain a satisfactory estimation of the strength of a toxine? As the constant factor
in such an estimation, it was only possible to proceed from a previously determined
standard reaction in the case of a definite species of animal, and so we came to regard as
the "toxic unit" that quantity of toxic
bouillon which exactly sufficed to kill, in the course of four days, a guinea-pig of 250
grammes weight.

When we employed this standard unit, or
"simple lethal dose," to estimate the amount of
toxic bouillon neutralised by one "immunity unit,"
the facts which presented themselves were far more surprising than it was possible to have
foreseen at the outset. These results were, that of one toxine, perhaps 20, of a second,
perhaps 50, and of yet a third, it might be 130 simple lethal doses were saturated by one
immunity unit.

Since, however, we had previously
assumed that the simple lethal dose alone afforded a standard on which reliance could be
placed in determining the combining relations of toxine and antitoxine, it appeared from
these results that the neutralisation of toxines by antitoxines did not follow the law of
equivalent proportions, and, notwithstanding all earlier work in agreement with such a
conception of the action, we were obliged to conclude that between toxine and antitoxine a
purely chemical affinity did not exist. The seemingly inexplicable contradiction between
the results just stated and previous work was very soon explained.

When the neutralisation point of toxine and
antitoxine was investigated for one and the same sample of poison, the following results
were obtained. Immediately on its preparation, fresh from the incubator, it was found that
one immunity unit neutralised a c.c. of toxic bouillon, and this quantity represented beta
simple lethal doses. When the same toxic bouillon was examined after a considerable
interval, the remarkable fact was discovered that exactly alpha c.c. of the toxic bouillon
were again neutralised by one immunity unit; but that these alpha c. c. now represented
only beta minus x simple lethal doses. It therefore followed that the toxic bouillon had retained exactly the same combining
affinity [in vitro],
but possessed feebler toxicity[in vivo]. From this it was evident that the toxic action on animals and the combining capacity with antitoxine
represented two different functions of the toxine, and that the former of these had become
weakened, while the latter had remained constant.

Treated from the chemical standpoint, this circumstance was most
simply explained by assuming that the toxine was characterised by the possession of two different combining groups: one, which may be designated haptophore, conditions the union with antitoxine,
while the other group, which may be designated toxophore,
is the cause of the toxic action. From the constancy of the combining capacity, and
the diminution in the toxicity, it was to be inferred that:

the toxophore
group was very unstable, but

the haptophore
group more stable, and also that

the deterioration of the toxophore
group proceeded of necessity quite independently of any relation to the haptophore group.

If we now designated
a toxine molecule, of which the toxophore group is destroyed, but its haptophore group
retained, as "toxoid," then the
above-described process will represent the quantitative progress of the conversion of the
toxine molecules into toxoid molecules. Such a toxoid molecule has the same quantitative
combining affinity for antitoxins as the original toxine molecule, in spite of the
disappearance of toxicity to the animal body. In other words, the affinity of the
haptophore group for the antitoxine is absolutely independent of the existence of a
toxophore group. Also, in the original toxine molecule, both
groups must be to such a degree non-related or independent of one another, that a mutual
reaction between them does not take place.

This conception of
the constitution of diphtheria toxine, after more extensive, very exact, and much varied
experimentation, based on its partial neutralisation by antitoxine, has been confirmed in
the completest manner possible. At this time it would be superfluous for me to enter into
all the details pertaining to these investigations. It need only be remarked that in
principle the same relations have been established for tetanolysine by Madsen, for
snake-poison by Meyers, and for the milk-curdling ferment by Morgenroth.

The separation of the characteristic atom groups of the toxine
molecule into a haptophore and a toxophore group, afforded not merely a satisfactory
chemical explanation of the process of neutralisation: the possession of the knowledge of
the existence of these groups yielded us, at the same time, the key to the nature of the
toxic property of toxines, and to the mystery of the origin of the antitoxines themselves.

After it had been
established by the already described method, that the toxine molecule was possessed of a
definite haptophore group, which accounted for its capacity to enter into combination with
other bodies, it was immediately necessary to inquire into the question whether, and if so
to what degree, this group entered into the causation of the symptoms of illness. That
chemical substances are only able to exercise an action on the tissue elements with which
they are able to establish an intimate chemical relationship is a conception of a general
nature, which has been entertained since the birth of scientific medicine.

It is astonishing, almost
astounding, that this axiom, of which the theoretical importance has been so long
recognised, and which has served indeed as the first ground for certain therapeutical
procedures, should as a matter of fact have played in the building up and furtherance of
scientific pharmacology a roleso
insignificant in proportion to its great importance. In glancing through the modern
text-books of pharmacology, with rare exceptions, as, e.g., Stokvis, one finds
absolutely no mention, of the distribution of drugs in the organism, a matter which is of
so much moment for arriving at a true comprehension of the relations existing between
pharmacological action, location in the organism, and chemical constitution. As a matter
of fact, the methods for obtaining any knowledge of the exact distribution of drugs in the
body are as yet very imperfect. Even if we can prove that certain alkaloids are again
recognisable as being, e.g., present in the brain, we are but little further advanced in
our knowledge of the process, because we cannot determine in which cells and which system
of fibres the alkaloid is localised.

I may say, indeed, that as
yet the investigation of the laws pertaining to the minute distribution of a chemical
substance in the body is only possible when, as in the case of coloured bodies, these are
at once recognisable by the eye. But that it is possible at once to draw conclusions of
therapeutic importance from the laws governing the distribution was shown in the case of
methylene-blue, in which I was able, knowing its distribution in the body, to anticipate
for it certain antineuralgic and antimalarial properties which were both established by
subsequent investigation.

It may be
permitted me to call to mind that in malaria methylene blue is especially of service in the case of persons who, on account of susceptibility, cannot be treated with quinine,
and that in the hands of Koch it has shown itself of eminent value in haemoglobinuric
fever, since as opposed to quinine it exercises no destructive action on the erythrocytes.
If we are not able to discover the principles governing the localisation of common
chemical bodies, which can be used in suitable quantities in chemical purity, and which
chemical and other reactions render perceptible, it was apriori very
unlikely that efforts directed to locating the toxines, which are potent in the slightest
traces, and which are bodies we have no means of rendering perceptible to our senses,
would be anything else than absolutely without result.

But that this is not so, has been shown by experiments carried out
by Professor Donitz, in the Steglitz Institute, to which, on account of their great
importance, I shall refer somewhat extensively. When a rabbit receives a suitable dose of
diphtheria or tetanus toxine injected directly into the circulation, the animal remains
for many hours well, and then begins to show symptoms of illness, which gradually increase
till they end in death.

In order to arrive at
an explanation of the incubation period, Donitz determined the amount of antitoxine which,
injected intravenously immediately after the toxine, absolutely neutralised the latter.
This neutralising dose is able to render all the toxine circulating in the blood
innocuous. When, however, the neutralising dose so determined was injected not
immediately, but seven or eight minutes after the injection of the toxine, death occurred
from tetanus exactly as if no antitoxine had been given.

Part of the toxine,
equal at least to the minimal lethal dose, must within this time have disappeared from the
blood, in which it would have been neutralised, and passed over to the tissues, especially
to the brain. The experiments of Donitz were afterwards confirmed by an investigation
conducted in quite a different manner by Heymans, who showed that a research animal from
which the blood had been removed immediately after the injection of the minimal lethal
dose of tetanus toxine, and replaced by transfusion of fresh blood, succumbed from typical
tetanus. In this case, therefore, in that brief interval of time the minimal lethal dose
of toxine had passed through the walls of the vessels and been taken up by the tissues.

Regarding the nature
of the processes here concerned, a satisfactory explanation was also afforded by the
experiments of Donitz. It admitted of demonstration that the toxine held in the tissues
could still be withdrawn from them, if not
the simple neutralising dose were injected, but larger quantities of the same.

The quantity necessary was
greater in proportion as the interval elapsing after the injection of the toxine was
longer. However, after a definite period was exceeded, all
possible doses of antitoxins, even the very greatest, were impotent,
notwithstanding that the animal at the time of the injection of the antitoxine had not
developed any symptoms.

Since a very great
number of other chemical substances, narcotics, alkaloids, and other neurotropic bodies,
were not in a position to withdraw the toxine once deposited in the central nervous
system, and as the property to do so was solely the characteristic of the specific
antitoxins, one was obliged to come to the conclusion that the union between the toxine and the tissues, which could only be overcome by
means of a specific chemically-related antagonising agent, must itself depend on a
chemical combination. One was therefore forced to accept the idea that the central nervous system, that is to say certain ganglion cells in it,
possessed atom groups resembling those of the antitoxins, in having a
maximum affinity for tetanus poison. The predilection of the nervous system for tetanus
toxine, the rapid union of the toxine with the nervous tissue, the gradual onset of the
symptoms and their long duration could only be explained by the existence of such toxophile groups. The statement of Donitz that the
tetanophile atom groups are in the guinea-pig essentially confined to the central nervous
system, whereas in the case of other species, especially rabbits, these are also present
in other organs, is one of prominent importance.

The beautiful experiments
of Roux on intracerebral injection of toxine have yielded absolute confirmation of the
statement of Donitz. Roux found in guinea-pigs that the same dose of tetanus toxine was
lethal, whether given by intracerebral or by subcutaneous injection; for rabbits, however,
the lethal dose was twenty times greater subcutaneously than it was in intracerebral
injection. This can only be explained in the terms of Donitz's observation, viz., that in
the case of direct injection of the toxine into the brain, the toxophile atom groups there
present at once seize on all the toxine, while when the toxine is administered through the
blood stream, the toxophile groups present in other organs also take up the toxine in
equivalent quantities. In the case of rabbits the absorption of the toxine in this way is
very considerable: indeed of twenty parts only one part finds its way into union
with the nervous system.

We
now come to the important question of the significance of
the toxophile groups in organs. That these are in function specially designed to seize on toxines cannot be for one moment
entertained. It would not be reasonable to suppose that there were
present in the organism many hundreds of atomic groups destined to unite with toxines,
when the latter appeared, but in function really playing no part in the processes of
normal life, and only arbitrarily brought into relation with them by the will of the
investigator. It would indeed be highly superfluous, for example, for all our
native animals to possess in their tissues atomic groups deliberately adapted to unite
with abrin, ricin, and crotin, substances coming from the far distant tropics.

One may therefore
rightly assume that these toxophile protoplasmic groups in reality serve normal functions
in the animal organism, and that they only incidentally and by pure chance possess the
capacity to anchor themselves to this or that toxine. [The following article in this web-page shows how, 50 years
later, this conceptual problem was overcome by Talmage and Burnet.]

The first thought suggested by this assumption [that toxophile groups serve a normal
function] was that the atom groups referred
to must be concerned in tissue change; and it may be well here to sketch roughly the laws
of cell metabolism. Here we must in the first place draw a clear line of distinction
between those substances which are able to enter into the composition of the protoplasm,
and so are really assimilated, and those which have no such capacity. To the first
class belong a portion of the food-stuffs parexcellence; to the second
almost all our pharmacological agents, alkaloids, antipyretics, antiseptics, &c.

How is it possible to
determine whether any given substance will be assimilated in the body or not ? There can
be no doubt that assimilation is in a special sense a synthetic process -- that is to say,
the molecule of the food-stuff concerned enters into combination with the protoplasm by a
process of condensation involving loss of a portion of its water. To take the example of
sugar, in the union with protoplasm, not sugar itself as such but a portion of it comes
into play, the sugar losing in the union some part of its characteristic combining
reactions. The sugar behaves here as it does, e.g., in the glucosides, from which
it canonly be obtained through the agency of actual chemical cleavage. The
glucoside itself yields no trace of sugar when extracted in indifferent solvents. In a
quite analogous manner, the sugar entering into the constitution of albuminous bodies
(glycoproteids) cannot be obtained by any method of extraction; at least, not until
chemical decomposition has previously taken place. It is therefore generally easy, by
means of extraction experiments, to decide whether any given combination in which cells
take part is, or is not, a synthetic one.

If alkaloids, aromatic amines, antipyretics, or aniline dyes be
introduced into the animal body it is a very easy matter, by means of water, alcohol, or
acetone, according to the nature of the body, to remove all these substances quickly and
easily from the tissues. This is most simply and convincingly demonstrated
in the case of the aniline dyes. The nervous system stained with methylene blue, or the
granules of cells stained with neutral red, at once yield up the dye in the presence of
alcohol. We are therefore obliged to conclude that none of the foreign bodies just
mentioned enter synthetically into the cell complex; but are merely contained in the cells
in their free state.

The combinations into
which they enter with the cells, and notably with the not really living parts of them
(Kupffer's paraplastic portions), are very unstable, and correspond usually only to the
conditions obtaining in solid solutions, while in other cases only a feeble salt-like
formation takes place. I myself in 1887 placed on a sure footing the fact that the nervous
system and the fatty tissues allow of alkaloids and aniline dyes being mechanically shaken
out of them, as in the poison-detection process of Stas and Otto.

Hence with regard to the pharmacologically
active bodies in general, it was not allowable to assume that they possessed definite atom
groups, which entered into combination with corresponding groups of the protoplasm.
This corresponds, as I may remark beforehand, with the incapacity
of all these substances to produce antitoxines in the animal body. We must
therefore conclude, that only certain substances,
food-stuffs par excellence, are, endowed with properties admitting of their
being, in the previously defined sense, chemically bound by the cells of the organism.

We may regard the cell quite
apart from its familiar morphological aspects, and contemplate its constitution from the
purely chemical standpoint. We are
obliged to adopt the view, that the protoplasm is equipped with certain atomic groups,
whose function especially consists in fixing to themselves certain food-stuffs, of
importance to the cell-life. Adopting the nomenclature of organic chemistry, these groups
may be designated side-chains.

We may assume that the protoplasm consists of a special executive
centre (Leistungs-centrum) in connection with which are nutritive side-chains, which
possess a certain degree of independence, and which may differ
from one another according to the requirements of the different cells.

And as these
side-chains have the office of attaching to themselves certain food-stuffs, we must also
assume an atom-grouping in these food-stuffs themselves, every group uniting with a
corresponding combining group of a side-chain. The relationship of the corresponding
groups, i.e., those of the food-stuff, and those of the cell, must be specific. They must be
adapted to one another, as, e.g., male and female screw (Pasteur), or as lock and
key (E. Fischer). From this point of view, we must contemplate the
relation of the toxine to the cell.

We have already shown that
the toxines possess for the antitoxines an attaching haptophore group, which accords
entirely in its nature with the conditions we have ascribed to the relation existing
between the food-stuffs and the cell side-chains. And the relation between toxine and cell
ceases to be shrouded in mystery if we adopt the view that the
haptophore groups of the toxines are molecular groups fitted to unite, not only with the
antitoxines, but also with the side-chains of the cells, and that it is by
their agency that the toxine becomes anchored to the cell

We do not, however,
require to suppose that the side-chains, which fit with the haptophore groups of the
toxines, i.e., the side-chains which are toxophile, represent something having no
function in normal cell economy. On the contrary, there is sufficient evidence that the
toxophile side-chains are the same as those which have to do with the taking up of the
food-stuffs by the protoplasm.

The toxines are, in
opposition to other poisons, of highly complex structure, standing in their origin and
chemical constitution in very close relationship to the proteids and their nearest
derivatives. It is, therefore, not surprising if they possess a haptophore group
corresponding to that of a food-stuff. Alongside of the binding haptophore group, which
conditions their union to the protoplasm, the toxines are possessed of a second group,
which, in regard to the cell, is not only useless but actually injurious. And we remember
that in the case of the diphtheria toxine there was reason to believe that there existed
alongside of the haptophore group another and absolutely independent toxophore group.

Now for certain cellular
elements of the body it can be proved in the test-tube that between these tissues and
certain toxines an "anchoring" process takes place
exactly similar to that between toxine and antitoxins. Wassermann first demonstrated this
in the case of the brain substance. In a mixture of tetanus toxine and broken-down fresh
guinea-pig brain the latter so bound or "anchored"
the toxine, that not only was the surrounding fluid toxine-free, but the brain substance
laden with the tetanus toxine had also lost its own toxic action, and so the mixture when
injected into an animal was borne without any harm.

The deduction is, that in
this case, a chemical union between the brain substance and the tetanus toxine had taken
place, andthis was of so firm a nature that on introduction into the body the
union was not broken up and therefore the toxine remained innocuous. The brain of the
normal animal had, in keeping with my theory, acted exactly like a real antitoxine. There
are present in the brain, i.e., in the gang lion cells, tetanophile protoplasmic groups,
which unite themselves with the toxine. The presence of such groups is the necessary
preliminary and cause of the poisonous action of the tetanus toxine in the living animal.
That the process here was not one of simple absorption is proved by the fact that, if the
group concerned was destroyed by heat, the brain substance became as incapable of removing
the toxine as an emulsion of any other organ of the guinea-pig.

As has been said, the
possession of a toxophile group by the cell is the necessary preliminary and cause of the
poisonous action of the toxine. This can be most sharply demonstrated in the case of
certain blood poisons, viz., the haemolysines,
which exercise a solvent action only on such red blood corpuscles as are able to unite
chemically with them. The union with the red corpuscles can be proved, and one has here
the great advantage of dealing with living and intact red blood cells instead of
broken-down cellular material. Under these conditions it is easy to determine the
quantitative relations of the union.

If we now
regard the action of the toxines with which we are concerned in accordance with the views
we have just been discussing, we are obliged to conclude that these are only in a position
to act prejudicially on the organism if they are able, by means of their haptophore
groups, to anchor themselves to the side-chains of the cells of organs essential to life.
If the cells of these organs lack side-chains fitted to unite with them, the toxophore
group cannot become fixed to the cell, which therefore suffers no injury, i.e., the
organism is naturally immune.

One of the most
important forms of natural immunity is based upon the circumstance, that in certain
animals the organs essential to life are lacking in those haptophore groups which seize
upon definite toxines. If, for example, the ptomaine occurring in sausages, which for man,
monkeys, and rabbits is toxic in excessively minute doses, is for the dog harmless in
quite large quantities, this is because, the binding haptophore groups being wanting, the
ptomaine cannot, in the dog, enter into direct relation with organs essential to life.

We see, then,
that the haptophore groups act especially in bringing definite areas of the cell within
the sphere of influence of the toxophore group. In the behaviour of the haptophore and
toxophore groups there exists a difference essentially great, as we have already pointed
out when referring to the work of Donitz and Heymans. The haptophore group exercises its activity immediately after injection into the organism, while in all toxines -- with
the, perhaps, solitary exception of snake-venom -- the toxophore group comes into activity
after the lapse of a longer or shorter incubation period, which may, e.g., in the case of diphtheria toxine,
extend to several weeks.

It is in the
highest degree interesting that it is possible, by voluntarily influencing certain of the
outside conditions, to exclude absolutely the action of the toxophore group. Courmont has
shown that frogs, when kept at a temperature lower than 20o C., manifest no
sign of tetanus, even after very large doses of tetanus toxine, but they succumb to fatal
tetanus if they are placed in surroundings of a higher temperature. Dr. Morgenroth,
working in my Institute, has throw light on this behaviour by proving that in frogs
maintained in cold surroundings the tetanus toxine is fixed in their central nervous
system, and that the absence of action at lower temperatures can only be explained by the
toxophore group of tetanus toxine having its action restricted within a certain
temperature minimum, while independent of this the haptophore group exercises its action
on the nervous system at all temperatures.

The
theory above developed allows of an easy and natural explanation of the origin of
antitoxines [see images 1-6]. In keeping with what has already been said, the first stage
in the toxic action must be regarded as being the union of the toxine by means of its
haptophore group to certain ''side-chains" of the cell
protoplasm. This union is, as animal experiments with a great number of toxines show, a
firm and enduring one.

The side-chain
involved, so long as the union lasts, cannot exercise its normal physiological nutritive
function -- the taking up of definite foodstuffs. It is as it were shut out from
participating, in the physiological sense, in the life of the cell. We are therefore now
concerned with a defect which, according to the principles so ably worked out by Professor
Carl Weigert, is repaired by regeneration. These principles, in fact, constitute the leading conception in my theory.

If, after union has taken
place, new quantities of toxine are administered at suitable intervals and in
suitable quantities, the side-chains, which have been reproduced by the regenerative
process, are taken up anew into union with the toxine, and so again the process of
regeneration gives rise to the formation of fresh
side-chains. In the course of the progress of typical systematic
immunisation, as this is practised in the case of diphtheria and tetanus toxine
especially, the cells become, so to say, educated or trained
to reproduce the necessary side-chains in ever-increasing quantity.

As Weigert has
confirmed by many examples, this, however, does not take place as a simple replacement of
the defect; the compensation proceeds far beyond the necessary limit; indeed,
over-compensation is the rule. Thus the lasting and ever-increasing regeneration must
finally reach a stage at which such an excess of side-chains
is produced that, to use a trivial expression, the side-chains are present in too great a
quantity for the cell to carry, and are, after the manner of a secretion, handed over as
needless ballast to the blood.

Regarded in accordance with
this conception, the antitoxines representnothing
more than side-chains reproduced in excess during regeneration,and therefore
pushed off from the protoplasm, and so coming to exist in afreestate.
With this explanation the phenomena of antitoxins formation lose all their strange,
one might say miraculous, characters.

I have
deemed it advisable to represent by means of some purely arbitrary diagrams (Plates 6 and
7 [images from which are reproduced here]) the views I have expressed regarding the
relations of the cell considered in the manner I have been describing. Needless to say,
these diagrams must be regarded quite apart from all morphological considerations, and as
being merely a pictorial method of presenting my views on cellular metabolism, and the
method of toxine action and antitoxine formation during the process of immunisation.

In the first place our
theory affords an explanation of the specific nature of the
antitoxines, that tetanus antitoxine is only caused to be produced by tetanus toxine, and
diphtheria antitoxine through diphtheria toxine. This very specific nature
of the affinity between toxine and cell is the necessary preliminary and cause of the
toxicity itself. Further, our theory makes it easy to understand the long-lasting character of the immunity produced by one or
several administrations of toxine, and also the fact that the organism reacts to relatively small quantities of toxine by the production
of very much greater quantities of antitoxine.

By
the act of immunisation, certain cells of
the organism become converted into cells
"secreting" antitoxine at the same rate as this is excreted. New
quantities of antitoxine are constantly produced, and so throughout a long period the
antitoxine content of the serum remains nearly constant. The secretary
nature of the formation of antitoxines has been very strikingly
illustrated by the beautiful experiments of Salmonson and Madsen, who have shown that
pilocarpine, which augments the secretion of most glands, also occasions in immunised
animals a rapid increase in the antitoxine content of the serum.

The production of antitoxines must, in keeping with our theory, be
regarded as a function of the haptophore group of the toxine, and it is
therefore easy to understand why, out of the great number of alkaloids, none are in a
position to cause the production of antitoxines. Conversely, indeed, I recognise in this
incapacity of the alkaloids, in opposition to the toxines, to produce antitoxines, a
further and salient proof of the truth of the deduction I have previously based on
chemical grounds, that the alkaloids possess no haptophore group which anchors them to the
cells of organs.

To formulate a
general statement, the capacity of a body to cause the
production of antitoxine stands in inseparable connection with the presence of a
haptophore atomic group. In the formation of antitoxine the toxophore
group of toxine molecule is, on the contrary, of absolutely no moment. But the toxoid modifications of the toxines, in which the haptophore
group of the toxine is retained, while its toxophore group has ceased to be active,
possess the property of producing antitoxines.

Indeed, in some cases of extremely
susceptible animals immunity can only be attained by means of the toxoids, and not by the
too strongly acting toxines. The toxoids are certainly able to cause the production of
antitoxines. To quote an example, it is hardly possible in an animal, which, like the
guinea-pig, has all the tetanophile groups confined to the cells of the central nervous
system, to produce immunity by means of the unaltered tetanus toxine, whereas this is
attained with extraordinary rapidity and ease by means of its toxoids.

The symptoms of illness due to the action
of the toxophore group, therefore, play no part in the production of antitoxine. On the
contrary, we may consider that the severe symptoms, which indicate injury to the
cell-life, disturb the regenerative functions, and thus hinder or entirely frustrate the
course of the immunisation process. I have from the first adopted this view, and it was
simply a misunderstanding when Knorr, who has beenall too soon taken from the
field of his labours, affirmed that, according to my theory, sickness of the cell
constituted the necessary condition precedent to the new formation and pushing-off of
side-chains.

If I
am not altogether deceived, the toxoids, where there is a question of producing active
immunization (and this will always be the case when the immunization concerns human
beings), are destined to play an important role
in practical medicine.

In
their theoretical relations the toxoids are also of far-reaching interest, in that they
provide a transition to that immunisation which can be called forth by substances which
would a priori be considered entirely devoid of toxic character, and which are
sometimes, like the autochthonous ferments (i.e., those normally present in blood),
products of normal cell-life, and in some cases food-stuffs proper.

Thus, Dr. Morgenroth, working in my laboratory, has proved that the rennet
ferment, if introduced ingreat quantitiesinto the organism, behaves
exactly like a real toxine, in that it causes the production of a typical anti-rennet,
which, up to a certain limit,accumulates in proportionally greater quantity, the
greater the injected doses.

Here, however, we
have to do with processes which are altogether within the region of the normal, as
is most clearly shown in certain animals, e.g., the horse, in the blood serum of
which there isnormally present
a quantity of anti-rennet, equal to that attained in the goat only after a systematic
immunisation carried on for months. The rennet ferment present naturally in the
body of the horse is the cause of this great formation of anti-rennet. According to
Bordet's experiments, if injections of milk be given to animals, their serum acquires
thereby the capacity to cause flocculent curdling. This action is seemingly rigidly
specific because (according to Morgenroth's experiments) the body produced by the
injection of goat's milk, coagulated goat's milk, but not human or cow's milk.

The behaviour is also
similar when different kinds of albumin, e.g. the sera of different animals or the
white of egg, are injected. There appear constantly in the serum of the animal so treated
new substances -- specific coagulines -- which act only in a specific manner, i.e.,
precipitate only the form of albumin injected. Thus there are produced, by the injection
of common food-stuffs, typical "Antikorper," which
unite with the substances used to occasion their production, and form with them insoluble
combinations.

My investigations have shown me that in the blood of animals which have not been subjected to any treatment we
must accept the presence of a number of normal bodies
analogous to the "Antikorper," having their origin in the most widely diverse
organs, and representing nothing more than nutritive side-chains, which in the course of
the normal nutritive processes have been developed in excess and pushed off into the
blood.

From all these
considerations I think myself warranted in concluding that the
formation of antitoxines lacks all the characters of that purposeful, intelligently
directed, and remarkable process which it at first seemed to be, and that
it is to be regarded merely as a process analogous to those constituting an essential
portion of the normal metabolism of the organism. We must admit that the majority of the
foodstuffs and of the intermediate products of tissue-change must be able to cause the
production and throwing-off of nutritive side-chains. It may be that the new formation
only takes place to a limited extent, and that the replacement of any side-chains which
have been shut out from their physiological function is all that is accomplished; but the
formation may occur in greater proportions, may become excessive, and therefore lead to
the presence of "Antikorper " in the blood.

In this way is easily
explained the fact of the occurrence in the normal blood serum of antitoxines and of
bodies inimical to bacteria, without the animals having ever been brought into relation
with the corresponding toxines or bacteria. Here I need only refer to the fact that
diphtheria antitoxine is not uncommonly present in normal horses and in men who have never
suffered from diphtheria.

Particularly weighty in this connection are the observations that
have been made on horses, because, on the one hand, these animals never suffer from
diphtheria, and, on the other hand, Cobbett has brought forward experimental proof that
this normally occurring antitoxine corresponds absolutely as to its properties with the
antitoxins produced by artificially immunising.

The conclusion,
therefore, is that in the body of the normal horse certain substances may be present which
possess side-chain affinities similar to those of the diphtheria toxine, and which,
therefore, are quite as capable as the latter are of taking possession of the cell
side-chains, and occasioning the regeneration and pushing-off of these from the cells; in
other words, of causing the presence of an actual diphtheria antitoxine in a normal
animal.

Such occurrences direct attention to the
possibility of producing immunity in some cases by the administration of definite
food-stuffs. Perhaps we have in some such peculiarity of feeding and tissue-change the
explanation of the fact so difficult to understand, viz., that individuals of the same
race and species react in such diverse manners to the same infection. Certainly we are
very far remove from the solution of this important question, which, as yet, has scarcely
assumed a tangible form. Still it is our duty to strive with tenacity to overcome the
difficulties which surround this point, bearing in mind the words of your illustrious
countryman, Francis Bacon: "Sunt certe ignavi regionum
exploratores, qui, ubi nil nisi coelum et pontus videtur, terras ultra esse prorsus negant."

I have now laid before you the fundamental facts which up to the
present constitute our knowledge in the field pertaining to immunity, and which can be
most easily and successfully explained through the agencyof "the side-chain theory." I wish in a few words to dispel some
erroneous ideas which have been advanced in opposition to this theory.

Roux has shown that
very small quantities of tetanus toxine, if injected directly into the brain, cause the
death of the animal. Roux assumes that such an occurrence is not compatible with my
theory. Roux is of opinion that according to my theory the brain must be quite immune
against tetanus toxine, as the toxophile side-chains of the brain-cells must be identical
with the antitoxine, and therefore exercise an immediate protective action. Experiment
showing quite the reverse, the theory is overthrown.

Roux came to this
incorrect conception through an erroneous conception of antitoxine. The toxophile
side-chains of the brain cells draw directly to themselves the toxine molecules, and,
according to my theory, are thus a necessary preliminary condition of the illness. The
toxophile groups are therefore really inducers of the action of the poison, and not its
preventives.

Those toxophile
groups which, like the antitoxines present in the serum,are able to lay hold of
toxine immediately on its entry into the blood, and so to divert it from organs essential
to life, can alone be regarded as being possessed of any antitoxic action in the true
sense of the word. I may be allowed to call to mind Weigert's excellent simile of iron and
the lightning conductor. Iron attracts electricity and is therefore used as a lightning
conductor. Great masses of iron present in buildings give rise to, or increase, the risk
of their being struck by lightning, and the metal only becomes protective against
lightning when it is so employed that the electricity is conducted away outside the
building.

It would never occur
to anyone to speak of great masses of iron machinery present in buildings as if they were
lightning conductors. It is equally unreasonable to speak of the antitoxic property of the
brain cortex, in which the toxophile groups are present in great quantity, but also retain
their relations with the nerve-cells. When this really considerable misunderstanding is
eliminated from Roux's results these become entirely confirmatory of my views, and it is
difficult to understand how, subsequent to Weigert having placed the matter in so clear a
light, the beautiful experiments of Roux can be utilised by another eminent authority as a
means of combating my theory.

Much more complex than in the cases hitherto discussed are the
conditions when, instead of the relatively simple metabolic products of microbes, the
living micro-organisms themselves come to be considered, as in immunisation against
cholera, typhoid, anthrax, swine fever, and many other infectious diseases. There then
come into existence alongside of the antitoxines, produced as a result of the action of
the toxines, manifold other reaction products.

This is because the
bacterium is a highly complicated living cell, of which the solution in the organism
yields a great number of bodies of different nature, in consequence of which a multitude of "Antikorper" are called into existence.
Thus we see, as a result of the injection of bacterial cultures, that there arise
alongside of the specific bacteriolysines, which dissolve the bacteria, other products,
as, for example, "coagulines" (Kraus, Bordet), i.e.,
substances which are able to cause the precipitation of certain albuminous bodies
contained in the culture fluid injected; also the so-much discussed "agglutinins" (Durham, Gruber, Pfeiffer), the antiferments (von
Dungern), and no doubt many other bodies which we have not yet recognised.

It is by no means
unlikely that each of these reaction
products finds itsorigin in special cells
of the body; on the other hand, it is quite likely that the formation of
any single one of these bodies is not of itself sufficient to confer immunity. Thus in
case of the introduction of bacteria into the body we have to do with a many-sided production of different forms of
"Antikorper," each of which is directed only against one definite quality or
metabolic product of the bacterial cell.

Accordingly, in
recent times, the practice of using for the production of immunisation definite toxic
bodies isolated from the bacterial cells has been more and more given up, and for this
purpose it is now regarded as important to employ the bacterial cells as intact as
possible. The beautiful results obtained for plague by Haffkine, and quite recently by
Wright in your own country for typhoid fever, have been arrived at in this way.

The most interesting and important substances arising during such
an immunising process are without doubt the bacteriolysines, in the investigation of which
Pfeiffer has done such yeoman's service. How really wonderful it is that after the
introduction of the cholera vibrio into the animal body a substance is formed endowed with
the power of dissolving the cholera vibrio, and that vibrio only!

This seemingly
purposeful and novel phenomenon seems at first sight to have nothing to do
with those forces which are normally at the disposal of the organism. It was of the
greatest importance to explain the origin of these substances from the standpoint of
cellular physiology. The solution offered very considerable difficulties, and was first
attained when, instead of bacteriolysines, haemolysines came to be employed in
experiments.

Haemolysines are peculiar toxic
bodies, which destroy red blood corpuscles by dissolving them. Haemolysines may occur in a
normal blood when they exercise a solvent action on the red blood corpuscles of other
species, or they may be artificially produced, in which case, after an animal has
undergone a process of immunisation against the blood corpuscles of another species, there
appear in the serum haemolysines which destroy the kind of blood corpuscles employed in
the production of the immunity. In their essential characters they are absolutely
comparable with the bacteriolysines: but they possess over them the great advantage that
they admit of being employed in test-tube experiments, and thus afford opportunity for
exact quantitative work altogether independent of the variability of the animal body.

Belfanti and Carbone
first discovered the remarkable fact that horses which have been treated with the blood
corpuscles of rabbits contain in their serum constituents which are poisonous for the rabbit, and for the rabbit only. While
the serum of the normal horse, to the quantity of 60 c.c., could be intravenously injected
without harm to the rabbit, a very few c.c. of serum from horses previously so treated
with rabbit's blood, proved fatal.

Bordet showed shortly thereafter, that in the case quoted there
was present in the serum a specific haemolysine which dissolved the blood corpuscles of
the rabbit. He also proved that these haemolysines -- as had already been shown by Buchner
and Daremberg in the case of similarly acting bodies which are present in normal blood --
lost their solvent property on being maintained during half
an hour at a temperature of 55oC. Bordet added,
further, the new fact, that the blood-solvent property of these sera which had been
deprived of solvent power by heat, the solvent action could be restored if certain normal sera were added to them.

By this important
observation an exact analogy was established with the facts of bacteriolysis as elicited
by the work of Pfeiffer, Metchnikoff, and Bordet. In the work on the Pfeiffer
phenomenon of bacteriolysis, it had already been ascertained that the solution of bacteria
by specific bacteriolysines was brought about by the combined
action of two different bodies: one which was specific, arose during the immunisation and
was stable; and another, a very unstable body, which was present in normal serum.

In collaboration with Dr. Morgenroth, I have sought in regard to this question, for whichhaemolysis
offered prospects favourable to experimentation, to make clear the mechanism
concerned in the action of these two components -- the stable,
which maybe designated "immune body," andthe unstable,
which may be designated "complement" -- which, actingtogether, effect the
solution of the red blood corpuscles. For this purpose, in the first place, solutions
containing either only the "immune body" or only
the "complement" were brought in contact with
suitable blood corpuscles, and after separation of the fluid and the corpuscles by
centrifugalising, we investigated whether these substances had been taken up by the red
blood corpuscles or remainedbehind in the fluid.

The proof of its
location in the one position or in the other was readily forthcoming, since to restore to
the haemolysine its former activity, it was only necessary to add to the "immunebody" a fresh supply of "complement," or to the "complement"
a fresh supply of "immune body," in order that the
presence of the haemolysine in its integrity might be shown by the occurrence of solution
of the blood-cells.

The experiments
proved that, after centrifugalising, the "immune
body" is quantitatively bound to the red blood corpuscles, and that
the "complement," on the contrary, remains
entirely behind in the fluid. The presence of the two components in
contact with blood corpuscles only occasions the solution of these at higher temperatures,
and not at 0oC. And an active haemolytic serum (with "immune body" and "complement"
both present) having been placed in contact with red blood corpuscles and maintained for a
while at 0oC., it was found after centrifugalising that, under these
circumstances also, the "immune body" had united
with the red blood corpuscles, but that the "complement"
remained in the serum. This experiment showed that both components must, at a temperature
of 0oC., have existed alongside of one another in a free condition. But when
analogous experiments were undertaken at a higher temperature it was found that both
components were retained in the sediment.

These facts can only be
explained by making certain assumptions regarding the constitution of the two components, i.e.,
of the "immune body" and the "complement." In the first place, two haptophore groups must be ascribed to the "immune body," one
having a great affinity for a corresponding haptophore group of the red blood corpuscles,
and with which at lower temperatures it quickly unites, and another haptophore group of a
lesser chemical affinity, which at a higher temperature becomes united with the
"complement" present in the serum.

Therefore,
at the higher temperature, the red blood corpuscles will draw to themselves those
molecules of the "immune body" which in the fluid
have previously become united with the "complement."
In this case the "immune body" represents in a
measure the connecting chain which binds the complement to the red blood corpuscles, and
so brings them under its deleterious influence. Since under the influence of the "complement" -- at least, in the case of the bacteria, --
appearances are to be observed (for example, in the Pfeiffer phenomenon) which must be
regarded as analogous to digestion, we shall not seriously err if we ascribe to this "complement" a ferment-like [enzymic] character.

It is obvious that
when the normal serum of one animal possess haemolytic action on the blood of another, the
component of the haemolysine which here unites with the red blood corpuscle and forms the
connecting link between it and the "complement"
which is essential to the occurrence of solution, cannot, in the absence of any preceding
process of immunisation, be designated "immune body."
In its characteristics and action, however, it only differs from this in occurring
naturally, and may well be designated "intermediate body" (Zwischenkorper; ["natural antibody"]). It may here be stated that the constitution of a haemolysine
is graphically represented in fig. 7, Plate 7 [see above].

Very important
for the conclusion that only with the assistance of the "intermediate
body" [natural
antibody] or of the "immune body" [induced antibody]
can the "complement," which leads to the solution,
become united with the blood corpuscle, is the following experiment.

The serum of the dog
has very considerable solvent action upon guinea-pig's blood, but loses this property if
warmed. If dog's serum, thus rendered inactive by warming, is brought into contact with
suspended corpuscles of guinea-pig's blood, these are not dissolved; but, if to such a
mixture there be also added guinea-pig serum, i.e., the serum normalto these red blood corpuscles, the
erythrocytes are at once dissolved. Here the only explanation is that the [natural antibody] "intermediate body,"
which possesses a specific affinity for guinea-pig erythrocytes, and is present in the
inactive dog's serum, is able to seize on one of the many "complements"
present in guinea pig's serum, with the result that the "complement"
which cannot normally attach itself to the corpuscles, comes now to, exercise its
destructive influence.

We see at the same
time from this experiment that the haemolysines occurring naturally,
obey the same laws as those produced through the process of immunising. In fact, for them
also, in a great number of instances, precisely similar behaviour has been demonstrated.

The character of the
specific union made it possible to find solutions for a number of important questions. In
the first place, regarding the multiplicity of the haemolysines, which occur normally in
serum, it is well known that numerous sera are able to dissolve blood corpuscles of
different species. For example, serum of the dog dissolves blood corpuscles of the rabbit,
guinea-pig, rat, goat, sheep, &c. The complex nature of these haemolysines has been
already indicated.

Another question arises whether, in a serum that is capable of
such manifold action, there is present one single haemolysine that destroys different red
blood cells, or whether a whole series of haemolysines come into action, of which
one is adapted to guinea-pig blood, another to rabbit blood, etc. The solution of this
question may be approached in another way. The serum may be rendered inactive by
heat, and then placed in contact with red blood corpuscles of a given kind.

Then, supposing, for example, that rabbit
blood has been employed, it is found that if the fluid is freed from the erythrocytes by
centrifugalisation and the "complement" afterwards
added, it is no longer in a position to dissolve rabbit blood, but has not suffered any
impairment of its action on other kinds.

By this method of elective absorptionit is proved that the
normally occurring haemolysines which chain the blood corpuscles of the rabbit to
themselves [cause them to
agglutinate], are specifically adapted to
this purpose. If with suitable adjustment of conditions similar experiments be conducted
with other kinds of blood, results are obtained which force us to the conviction that in
such a serum acting on various kinds of blood there are present absolutely different [natural antibodies] "intermediate bodies"
(analogues of the "immune bodies"), of which each
one is specific for one kind of blood, i.e., one is adapted for rabbit's blood, a
second for calf's blood, etc. Dr. Morgenroth and I have in some cases, indeed, succeeded
in proving that the "complements" which are adapted
to fit themselves to these [natural
antibodies] "intermediate
bodies", and occur in normal sera, differ among themselves. If we reflect that
in normal blood, in addition to these different haemolysines, there are besides a long
series of analogous bodies, agglutinines of very different kinds, bacteriolysines,
enzymes, anti-enzymes, we are brought more and more to the conviction that the blood serum is the carrierof
substances innumerable as yet little known or conceived of.

Having obtained a precise conception of the method of action of the lysines of the
serum -- of the haemolysines, and thereby also of the bacteriolysines -- it becomes
possible for us to attempt to solve the mystery of the
origin of these bodies. I have in the beginning of this lecture fully
developed the "side-chain theory," according to
which the antitoxines [antibodies] are merely certain of the protoplasm, "side-chains," which have been produced in excess and pushed
off into the blood.

The toxines [antigens], as secretion products of cells, are in all likelihood still
relatively uncomplicated bodies; at least by comparison with the primary and complex
albumins of which the living cell is composed. If a cell of the organism has, with the
assistance of an appropriate "side chain," fixed to
itself a giant molecule, as the proteid molecule really is, then, with the fixation of
this molecule, there is provided one of the conditions essential for the cell nourishment.

Such giant
molecules cannot at first be utilised by the cells, and are only made available when, by
means of a ferment-like [enzymic] process, they are split into smaller fragments. This will be
very effectually attained if, figuratively speaking, the "tentacle"
or grappling arm of the protoplasm possesses a second haptophore group adapted to take to
itself ferment-like material out of the blood fluid. Through such complex organisation, by
which the "tentacle" acts also as the bearer of a
ferment-functioning group, this group is brought into close relation with the prey
destined to be digested and assimilated.

For such appropriate arrangements, in which the "tentacular" apparatus also exercises a digestive function --
if it be permissible to pass from the abstract to the concrete -- we find analogies in the
different forms of insectivorous plants. Thus it has been known since the famous
researches of Darwin that the tentacles of Drosera secrete a proteid-digesting fluid.

If, we now recognise
that the different lysines only arise through absorption of highly complex cell material
-- such as red blood corpuscles or bacteria -- then the explanation, in accordance with
what I have said, is that there are present in the organism
"side-chains" of a special nature, so constituted that they are
endowed not only with an atomic group by virtue of the affinities of which they are
enabled to pick up material, but also with a second atomic group, which, being
ferment-loving in its nature, brings about the digestion of the material taken up. Should
the pushing-off of these "side chains" be forced,
as it were, by immunisation, then the "side-chains"
thus set free must possess both groups, and will therefore in their characteristics
entirely correspond to what we have placed beyond doubt as regards the "immune-body" of the haemolysine.

In this manner is
simply and naturally explained the astonishingly specialised arrangement that, through the
introduction of a definite bacterium into the body, something is produced which is endowed
with the power of destroying by solution the bacterium which was administered and no
other. This contrivance of the organism is to be regarded as nothing more than a
repetition of a process of normal cell-life, and the outcome
of primitive wisdom on the part of the protoplasm.

In conclusion, I wish hastily to touch on only a few points.
First, to direct attention to the fact that the immunising sera produced by the
administration of bacteria are sometimes limited in their operation to certain animal
species, and are much more inconstant in their action than are the antitoxines.
Sobernheim, in the laboratory of C. Fraenkel, found that the anthrax serum obtained by
immunising German marmots (Hamster) protected this species, even in small doses; but was
absolutely without action for rabbits. Kitt had a precisely similar experience with
symptomatic anthrax.

This circumstance is
easy to understand, if the complex nature of the lysines be borne in mind. The lysine, be
it bacteriolysine or haemolysine (i.e., "immune body"
+ "complement"), possesses altogether three
haptophore groups, of which two belong to the "immune-body"
and one to the "complement." Each one of these
haptophore groups can be bound by an appropriate "anti-group".
Three anti-groups are thus conceivable, any one of which, by uniting with one of the
haptophore groups of the lysine, can frustrate the action of the lysine. To my mind, of
these three possible "Antikorper," that one which
can lay hold of the haptophore group of the "complement,"
and so prevent this from uniting with the "immune body,"
is the most important. Dr. Morgenroth and I have experimentally succeeded in producing
such bodies by processes of immunisation, and in proving that they unite with the "complement" (anticomplement).

Dr. Neisser at
the Steglitz Institute sought to find an explanation of Sobernbeim's experiments. He was
able to determine that anthrax serum failed in mice, even if great quantities of fresh
sheep's serum (i.e., containing excess of "complement")
were at the same time introduced. The failure in this case appears to be due, on the one
hand, to the destruction, in the body of the mouse, of the "complement"
present in the sheep's serum, and, on the other hand, to the fact that the "immune body" yielded by the sheep does not find in mouse serum
an appropriate new "complement."

From this
it appears, that in the therapeutic application of antibacterial sera to man,
therapeutical success is only to be attained if we use either a bacteriolysine with a
"complement" which is stable in man ("anthropostabile complement"), or at least a bacteriolysine,
the "immune body" of which finds in human serum an
appropriate "complement." The latter condition will
be the more readily fulfilled the nearer the species employed in the immunisation process
is to man.

Perhaps the
non-success which as yet has attended the employment of typhoid and cholera serum will be
converted into the contrary if the serum be derived from apes and not taken from species
so distantly removed from man as the horse, goat, or dog. However this may be, the
question of the provision of the appropriate "complement"
will come more and more into the foreground, for it really represents the centre round
which the practical advancement of bacterial immunity must turn.

A
second and at present much-discussed question, is the immunising of the organism against
elements standing biologically much higher in the scale than erythrocytes and much less
foreign to the body than those exceedingly lowly organisms, the bacteria. I refer here to
the production of "Antikorper" against cells of the
higher animal organisation, e.g., ciliated epithelium (v. Dungern), spermatozoa
(Landsteiner, Metchnikoff, Moxter), kidney cells, and leucocytes. These "Antikorper" are also of a complex nature. They obey the already described law of elective absorption, and their
origin is in keeping with the "side-chain" theory. It is to be
hoped that such immunisations as these, which are of great theoretical interest, may also
come to b available for therapeutic application.

The idea has already been mooted by v. Dungern,
of attacking epithelial new formations, partictularly carcinoma, by means of specific
"antiepithelial sera," and
Metchnikoff has expressed the somewhat bold hope of being able to delay old age by means
of a serum directed against phagocytes (macrophages). But even if in the immediate future
no great practical success is attained, we must remember that we are only at the very beginning of a rational investigation of
properties of cells which hitherto have been far too lightly regarded.

The sifting of the material
obtained by observation is rendered more difficult by the occurrence under normal
conditions of a great number of quite unlooked for bodies furnished with haptophore groups
and arising from diverse organs, and which we may designate collectively as haptines. It is to be expected that the study
of these haptines will not only throw light on the more minute details of cellular
metabolism, but also prove fruitful in the fields of pathology and therapeutics.

By the fact that we
can cause the individual haptines of the cells to pass out into the blood serum by a
process of specific immunisation, it becomes possible in the test-tube to analyse more
accurately the mode of operation of their binding groups than is possible in the case of
the complicated conditions which present themselves in the animal body. The importance,
for the study of immunity, of considering the circumstances from a purely cellular standpoint is evident from all
that I have said.

I trust, my lords and
gentlemen, that from what I have said you may have obtained the impression, to allude
again to my quotation from Bacon, that we no longer find ourselves lost on a boundless
sea, but that we have already caught a distinct glimpse of the land which we hope, nay,
which we expect, will yield rich treasures for biology and therapeutics.

I desire to express my indebtedness to
Dr. E. F. Bashford, McCosh Scholar of the University of Edinburgh, now working with me in
my Institute, for his kindness in undertaking the translation of my lecture into English,
a task to which he has devoted much time and trouble.

Some additional viewpoints on
Ehrlich's work

Lederberg, J, (1988) " Ontogeny of the clonal selection
theory of antibody formation. Reflections on Darwin and Ehrlich. Annals New York Academy of Sciences546, 175-182.

David Talmage kindly provided photographs. Photographs of some other protagonists
may be viewed in the image collection of the History of Medicine Division of the National
Library of Medicine, USA. Click here for Image
Collection. The MHC figure was, with permission, from Colin Hewitt's fine web-page (Click here).